US7662777B2 - Use of sulglicotide for the treatment of mucositis - Google Patents
Use of sulglicotide for the treatment of mucositis Download PDFInfo
- Publication number
- US7662777B2 US7662777B2 US11/569,095 US56909505A US7662777B2 US 7662777 B2 US7662777 B2 US 7662777B2 US 56909505 A US56909505 A US 56909505A US 7662777 B2 US7662777 B2 US 7662777B2
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- US
- United States
- Prior art keywords
- sulglicotide
- treatment
- mucositis
- cells
- mean
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
Definitions
- Mucositis is a common inflammatory condition affecting the mucous membranes, in particular following chemotherapy or radiotherapy in patients suffering from tumours.
- the oral cavity is one of the areas which is highly affected by the complications arising from such treatment; indeed, virtually all patients treated for tumours of the head and neck, and around 40% of those subjected to radio-chemotherapy for tumours in other locations (leukaemias or lymphomas) develop complications affecting the oral cavity (Minerva Stomatol. 2002:51:173-86).
- macositis is understood to mean a clinical picture characterised by the presence of reduced epithelial thickness, intense erythema and ulcers, associated with a painful symptom complex and the possible occurrence of infection and haemorrhage (Oncologist 1998:3:446-52; Oncologist 1999:11:261-6).
- the biological mechanism underlying the development of mucositis is subdivided into four phases: an initial inflammatory/vascular phase during which, following radio- or chemotherapy, the epithelial tissues release a large quantity of cytokines such as, for example, interleukin 1 or TNF- ⁇ , which cause the first localised tissue damage; a second epithelial phase which affects the division of the epithelial basal cells, resulting in reduced renewal of said cells, atrophy and ulceration of the tissue; a third ulcerative/bacterial phase, which is when the symptoms are at their most intense, with bacterial colonisation of the lesion.
- cytokines such as, for example, interleukin 1 or TNF- ⁇
- This third phase also coincides with severe neutropaenia of the patient; the fourth and final characteristic phase of mucositis is considered to be the healing phase with recovery of proliferation and differentiation of epithelial cells, a progressive increase in white cells and normalisation of the local bacterial flora.
- agents are used which are capable of reducing mucous absorption of the chemotherapy drugs (for example cryotherapy, allopurinol or pilocarpine etc.), agents which reduce the changes in epithelial proliferation (for example beta-carotene, glutamine or silver nitrate etc.) or antiinflammatory and antimicrobial agents (for example, mesalazine and/or chlorhexidine).
- chemotherapy drugs for example cryotherapy, allopurinol or pilocarpine etc.
- agents which reduce the changes in epithelial proliferation for example beta-carotene, glutamine or silver nitrate etc.
- antiinflammatory and antimicrobial agents for example, mesalazine and/or chlorhexidine.
- cryotherapy is today the most widely recognised preventive treatment; this method is based on the administration of ice cubes to be kept in the mouth for a period of 30 minutes with the aim of bringing about vasoconstriction of the oral mucosa in order to reduce the temperature-dependent toxicity of some chemotherapeutics.
- cryotherapy has proved to exhibit substantial preventive effectiveness only in patients treated with chemotherapeutics which can be administered as a bolus (fluorouracils) but has proved ineffective for continuously perfused chemotherapeutics because the drug is permanently present in the circulating blood and local vasoconstriction locale is of no benefit (Oral Oncology 1999; 35:453-70).
- agents which protect the mucosa for example, sodium bicarbonate
- anaesthetic or analgesic agents for example, lidocaine, morphine and the derivatives thereof etc.
- agents which accelerate the healing process for example, vitamin E, tretinoin, laser therapy etc.
- special diets and/or specific oral hygiene regimens for example, vitamin E, tretinoin, laser therapy etc.
- Sulglicotide is a sulfuric polyester of a glycopeptide obtained by extraction from pig duodenum. Sulglicotide is obtained by enzymatic proteolysis, repeated purification and subsequent sulfation steps; the final product is identified by electrophoresis on cellulose acetate.
- Sulglicotide is a gastroprotective and antiulcer drug; it is not absorbed intestinally and is known to produce its effects only within the gastric lumen.
- sulglicotide is usually administered as a gastroprotective to individuals whose stomach wall has been attacked by drugs such as, for example, aspirin and taurocholic acid or by generic nonsteroidal antiinflammatory drugs.
- drugs such as, for example, aspirin and taurocholic acid or by generic nonsteroidal antiinflammatory drugs.
- Clinical studies have demonstrated the effectiveness of administering sulglicotide to patients suffering from rheumatoid arthritis and receiving treatment with indomethacin and diclofenac, so preventing the occurrence of gastric or duodenal ulceration associated with the use of such nonsteroidal antiinflammatories (Scand. J. Gastroenterol. 1993; October; 28(10):875-8).
- the mechanism of action apart from being linked to pepsin inactivation, is due to the stimulation of the secretion of mucous and bicarbonate by the cells of the gastric mucosa.
- sulglicotide is known to be the drug of choice for the treatment of gastric conditions associated with Helicobacter pylori inflammation.
- Helicobacter pylori is a spiral-shaped, gram-negative bacterium which, thanks to its various characteristics, survives in the acidic environment of the gastric mucosa and proliferates under the mucous which coats the internal wall of the stomach, adhering to the cells of the mucosa itself. It is the cause of duodenal ulcers as well as being one of the main causes of chronic gastritis. Current treatments are based on antibiotics and, in the ever more frequent event of antibiotic-resistant strains and relapse, on specific antiulcer drugs.
- Sulglicotide principally acts by inhibiting the effect of the LPS (lipopolysaccharide) produced by the bacterium which prevents somatostatin-receptor binding, causing overproduction of gastrin and acidic secretions which are responsible for the subsequent formation of the ulcer.
- LPS lipopolysaccharide
- suiglicotide in the treatment of mucositis brings about a considerable improvement with regard to the inflammatory symptom complex and to mucosal damage, with functioning of epithelial cells being significantly restored.
- sulglicotide exhibits its effectiveness in the treatment of mucositis of the oral cavity. More particularly, sulglicotide is active in the treatment of mucositis due to chemotherapy and/or radiotherapy.
- Sulglicotide by increasing levels of both type PGE 2 and type PGI 2 prostaglandins, brings about increased secretion of mucous and normalised renewal of the epithelial cells of the mucosa. Furthermore, sulglicotide is capable of increasing the secretion of EGF (Epidermal Growth Factor) and so ensuring both the onset of much less severe conditions of the mucosa, and the acceleration of the healing process of such conditions.
- EGF Epidermal growth Factor
- EGF EGF
- the increase in the quantity of EGF, or of the receptor thereof brings about increased proliferation of the epithelial cells with the formation of a superstratum of said cells and consequent thickening of the mucosa, in particular the oral and/or gastrointestinal mucosa, which is so able to act as a barrier to attack from cytotoxic agents (for example radiation) and significantly reduce any damage.
- EGF growth factors
- tumours such as tumours of the head and neck (for example laryngeal, pharyngeal or oesophageal carcinoma)
- tumours such as tumours of the head and neck
- tumours of the head and neck for example laryngeal, pharyngeal or oesophageal carcinoma
- sulglicotide is active in the prevention and treatment of mucositis, in particular oral mucositis due to antitumour treatments such as chemotherapy and/or radiotherapy.
- FIG. A is an illustration of the morphology of a normal intestinal crypt.
- FIG. B is an illustration of the morphology of an intestinal crypt after irradiation with centers of regeneration.
- FIG. C is an illustration of the morphology of an intestinal crypt containing fewer than 10 cells.
- Animal testing was carried out with the aim of assessing the efficacy of suiglicotide in protecting the clonogenic cells of the intestinal mucosa from radiation-induced damage. Protection of the clonogenic cells ensures the survival of the intestinal crypt which promotes the restoration of the normal epithelium.
- the animals treated in the present test are free from H. pylori , or their gastrointestinal mucosa does not exhibit the characteristic signs of inflammation brought about by this bacterium.
- the inflammatory damage was caused by a 13 Gy X-ray dose. 60 male BDF1 mice, divided into 10 groups each of 6 animals, were treated.
- Sulglicotide was administered daily as a preventive measure to 4 groups (plus one control/saline solution group) via a gastric tube and at various doses, namely respectively 12 mg/kg, 50 mg/kg, 200 mg/kg and 800 mg/kg three days before irradiation with a final dose 30 minutes before irradiation.
- the other 4 groups received sulglicotide as a treatment, again via a gastric tube and at various doses, namely respectively 12.5 mg/kg, 50 mg/kg, 200 mg/kg and 800 mg/kg immediately after irradiation and thereafter daily for 3 days before sacrifice on the 4th day.
- FIG. A The attached Figures show the normal intestinal morphology (Fig. A) or after irradiation with centres of regeneration in which surviving crypts can be seen with only one or more clonogenic cells and the remaining mesenchyme completely lacking (Fig. B). These individuals develop diarrhoea and die from mucositis.
- Figure C shows an intestinal morphology with phantom crypts or crypts containing fewer than 10 cells.
- sulglicotide On irradiation damage and the association between efficacy and the different dose administered.
- sulglicotide does not exhibit any preventive effect on the damage to clonogenic cells and the intestinal crypts; evidence of increased survival of the crypts and thus of protection from irradiation damage is found at a dose of 200 mg/kg (35%).
- a dose of greater than 200 mg/kg also exhibits no protective efficacy.
- the dose of 200 mg/kg exhibits no activity in the post-irradiation treatment groups.
- sulglicotide administered to mice free from Helicobacter pylori via a gastric tube at various doses, proves to be effective in the prevention or treatment of radiation damage.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Marine Sciences & Fisheries (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2004A0989 | 2004-05-18 | ||
IT000989A ITMI20040989A1 (it) | 2004-05-18 | 2004-05-18 | Uso del sulglicotide per iul trattamento delle mucositi |
ITMI2004A000989 | 2004-05-18 | ||
PCT/IT2005/000272 WO2005110458A1 (en) | 2004-05-18 | 2005-05-12 | Use of sulglicotide for the treatement of mucositis |
Publications (2)
Publication Number | Publication Date |
---|---|
US20080234180A1 US20080234180A1 (en) | 2008-09-25 |
US7662777B2 true US7662777B2 (en) | 2010-02-16 |
Family
ID=34971240
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/569,095 Expired - Fee Related US7662777B2 (en) | 2004-05-18 | 2005-05-12 | Use of sulglicotide for the treatment of mucositis |
Country Status (9)
Country | Link |
---|---|
US (1) | US7662777B2 (it) |
EP (1) | EP1747010B1 (it) |
JP (1) | JP4874962B2 (it) |
CN (1) | CN1972705B (it) |
BR (1) | BRPI0511165A (it) |
CA (1) | CA2565084C (it) |
IL (1) | IL178907A0 (it) |
IT (1) | ITMI20040989A1 (it) |
WO (1) | WO2005110458A1 (it) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10806752B2 (en) | 2017-01-13 | 2020-10-20 | Imdpharm Inc. | Pharmaceutical composition containing sulglycotide or pharmaceutically acceptable salt thereof for preventing or treating dry eye |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101851285B (zh) * | 2009-04-03 | 2012-09-12 | 四川德博尔制药有限公司 | 硫酸糖肽的制备方法 |
CN115845127B (zh) * | 2022-12-29 | 2023-11-24 | 海南众森生物科技有限公司 | 一种多糖止血修复生物胶液及其制备方法和用途 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0274745A1 (en) | 1987-01-12 | 1988-07-20 | Crinos Industria Farmacobiologica S.p.A. | Pharmaceutical composition for the prophylaxis and therapy of gastric ulcer |
WO1992018153A1 (en) | 1991-04-12 | 1992-10-29 | Creative Biomolecules, Inc. | Method of treating gastrointestinal ulcers with platelet derived growth factor |
US5496828A (en) | 1994-08-22 | 1996-03-05 | Eli Lilly And Company | Methods of inhibiting ulcerative mucositis |
US20030064913A1 (en) | 2001-08-16 | 2003-04-03 | Sonis Stephen T. | Treatment and prevention of mucositis in cancer patients |
US20030236217A1 (en) | 2002-05-21 | 2003-12-25 | Shalwitz Robert A. | Treatment of mucositis |
-
2004
- 2004-05-18 IT IT000989A patent/ITMI20040989A1/it unknown
-
2005
- 2005-05-12 JP JP2007517663A patent/JP4874962B2/ja not_active Expired - Fee Related
- 2005-05-12 WO PCT/IT2005/000272 patent/WO2005110458A1/en active Application Filing
- 2005-05-12 CA CA2565084A patent/CA2565084C/en not_active Expired - Fee Related
- 2005-05-12 US US11/569,095 patent/US7662777B2/en not_active Expired - Fee Related
- 2005-05-12 BR BRPI0511165-0A patent/BRPI0511165A/pt not_active IP Right Cessation
- 2005-05-12 CN CN2005800159271A patent/CN1972705B/zh not_active Expired - Fee Related
- 2005-05-12 EP EP05742993.8A patent/EP1747010B1/en not_active Not-in-force
-
2006
- 2006-10-26 IL IL178907A patent/IL178907A0/en not_active IP Right Cessation
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0274745A1 (en) | 1987-01-12 | 1988-07-20 | Crinos Industria Farmacobiologica S.p.A. | Pharmaceutical composition for the prophylaxis and therapy of gastric ulcer |
US5085867A (en) * | 1987-01-12 | 1992-02-04 | Crinos Industria Farmacobiologica S.P.A. | Method for treating gastric ulcer with sulglycotide and hydrophilic polymer |
WO1992018153A1 (en) | 1991-04-12 | 1992-10-29 | Creative Biomolecules, Inc. | Method of treating gastrointestinal ulcers with platelet derived growth factor |
US5496828A (en) | 1994-08-22 | 1996-03-05 | Eli Lilly And Company | Methods of inhibiting ulcerative mucositis |
US6274601B1 (en) * | 1994-08-22 | 2001-08-14 | Eli Lilly And Company | Methods of inhibiting ulcerative mucositis |
US20030064913A1 (en) | 2001-08-16 | 2003-04-03 | Sonis Stephen T. | Treatment and prevention of mucositis in cancer patients |
US20030236217A1 (en) | 2002-05-21 | 2003-12-25 | Shalwitz Robert A. | Treatment of mucositis |
Non-Patent Citations (11)
Title |
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Database Biosis 'Online! Biosciences Information Service, 1995, "Enhancement in gastric mucosal EGF and PDGF receptor expression with ulcer healing by sulglycotide" Abstract. |
Demarosi, F. et al, Prevention and Treatment of Chemo- and Radiotherapy-Induced Oral Mucositis, Minerva Stomatologica, 2002, pp. 173-186, vol. 51. |
Peterson, Douglas E., Research advances in oral mucositis, Current Opinion in Oncology, 1999, pp. 261-266, vol. 11. |
Pico, J., et al, Mucositis: Its Occurrence, Consequences, and Treatment in the Oncology Setting, The Oncologist, 1998, pp. 446-451, vol. 3. |
Piotrowski et al. Enhancement in Gastric Mucosal EGF and PDGF Receptors Expression with Ulcer Healing by Sulglycotide, 1995, Genral Pharmacology, vol. 26, No. 4, pp. 749-753. * |
Plevova, P., Prevention and treatment of chemotherapy- and radiotherapy- induced oral mucositis: a review, Oral Oncology, 1999, pp. 453-470, vol. 35. |
Porro, G. B., et al, Sulglycotide in the Prevention of Nonsteroidal Anti-inflammatory Drug-Induced Gastroduodenal Mucosal Injury, Sulglycotide in Preventing Mucosal Injury, 1993, pp. 875-878, vol. 28 (10). |
Slomiany et al. Omerazole Failsto Suppress Up-Regulation of Gastric Mucosal Endothelin-Converting Enzyme-1 by Helicobacter Pylori Lipopolysaccharide, 2000, Journal of Physiology and Pharmacology, vol. 51, No. 3, pp. 421-431. * |
Slomiany et al. Suppression of gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide by sulglycotide, 1999, General Pharmacology, vol. 32, pp. 251-257. * |
Slomiany, B.L., et al, Endothelin-1, Interleukin-4 and Nitric Oxide Synthase Modulators of Gastric Mucosal Injury by Indomethacin: Effect of Antiulcer Agents, Journal of Physiology and Pharmacology, 1992, pp. 197-210, vol. 50 (2). |
Sonis, S.T., Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity, Oral Oncology, 1998, pp. 39-43, vol. 34. |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10806752B2 (en) | 2017-01-13 | 2020-10-20 | Imdpharm Inc. | Pharmaceutical composition containing sulglycotide or pharmaceutically acceptable salt thereof for preventing or treating dry eye |
Also Published As
Publication number | Publication date |
---|---|
IL178907A0 (en) | 2007-03-08 |
CN1972705B (zh) | 2011-11-02 |
ITMI20040989A1 (it) | 2004-08-18 |
US20080234180A1 (en) | 2008-09-25 |
JP2007538066A (ja) | 2007-12-27 |
CA2565084A1 (en) | 2005-11-24 |
EP1747010B1 (en) | 2015-01-21 |
BRPI0511165A (pt) | 2007-12-04 |
CN1972705A (zh) | 2007-05-30 |
CA2565084C (en) | 2013-09-03 |
WO2005110458A1 (en) | 2005-11-24 |
JP4874962B2 (ja) | 2012-02-15 |
EP1747010A1 (en) | 2007-01-31 |
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